Recent evidence from two independent lines of investigation has merged to suggest that neoplasia results from the abnormal activation of a relatively small number of cellular genes. Certain retroviruses contain transduced cellular genes which infer transforming properties to the retrovirus. The retroviruses containing these cellular sequences in their genome can induce tumors in animals or transform cells in vitro. Subsequent studies have established that proto-oncogenes can also be activated as oncogenes in naturally occurring tumor cells by mechanisms completely independent of retroviral involvement. These genetic alterations range from point mutations to gross DNA rearrangements such as translocation and gene amplification. We have recently initiated studies to investigate oncogene activation and expression in spontaneous and chemical-induced tumors in rodents. Comparison of types and extent of oncogene activation in spontaneous versus chemically-induced tumors may aid in risk assessment of chemicals based on bioassay data obtained from various animal model systems. In addition, animal model systems must be developed to study the sequence of oncogene activation and expression.